Clinical Reasoning: A case of bilateral foot drop in a 74-year-old man

Section 1

A 74-year-old man with no relevant medical history presented with 5 years of slowly progressive bilateral foot drop. He had used ankle foot orthoses for 3 years prior to presentation. There was no report of upper extremity weakness, numbness, paresthesia, myalgias, muscle cramps, or stiffness. He had attained age-appropriate developmental milestones as a child and was athletic, keeping up with his peers. His mother had bilateral foot drop, ankle contractures, and difficulty with ambulation. His brother, 2 daughters, and a son lacked similar symptoms. Neurologic examination showed bilateral distal lower extremity weakness (Medical Research Council grade 0/5 ankle dorsiflexion and eversion and grade 4/5 ankle plantar flexion and inversion), symmetric distal leg and intrinsic foot muscle wasting, absent patellar and Achilles tendon reflexes, and a steppage gait. Tone was reduced at bilateral ankles. Sensory examination including light touch, pinprick, vibration, and proprioception was intact. Mild bilateral pes cavus and hammertoes were noted. The remainder of the neurologic and physical examination was normal.

Section 2

Foot drop is primarily caused by the weakness of the tibialis anterior muscle that produces ankle dorsiflexion. A systematic approach through anatomical localization is critical to determine the origin of foot drop. CNS disorders involving the brain or spinal cord uncommonly manifest with pure, bilateral foot drop. The tibialis anterior muscle is predominantly innervated by the L5 nerve root. Spinal cord lesions above L5 can cause bilateral foot drop. However, the absence of upper motor neuron signs or other features of spinal cord dysfunction in our patient argue against these. Anterior horn cell disorders also cause foot drop. Amyotrophic lateral sclerosis is unlikely due to the absence of upper motor neuron signs, fasciculations or bulbar involvement, and the very slow rate of progression. Progressive muscular atrophy that only affects lower motor neurons commonly presents with asymmetrical segmental involvement, though symmetrical involvement of distal muscles has been described.¹ Bilateral L5 radiculopathies or lumbosacral plexopathy may also cause bilateral foot drop. However, the absence of sensory symptoms, pain, or weakness in proximal L5 myotomes in our patient is atypical. Peripheral nerve lesions involving bilateral sciatic or peroneal (fibular) nerves that innervate the tibialis anterior muscles is a possibility. The peroneal nerves are susceptible to compression at the fibular head. Associated sensory involvement is typically seen. A lack of a history suggesting compression of the peroneal nerves, the absence of sensory symptoms or signs, and the associated ankle inversion and plantar flexion weakness (innervated by the tibial nerve) make compression at the fibular head an unlikely etiology. Similarly, the absence of sensory findings or hamstring weakness argue against a localization to the sciatic nerves. Polyneuropathy (hereditary or acquired) is also a common cause of foot drop. The pure motor clinical phenotype limits the range of possible peripheral neuropathies. Multifocal motor neuropathy may cause a chronic distally accentuated motor neuropathy and foot drop, but the symmetrical presentation and family history favor a distal hereditary motor neuropathy (dHMN). The most common form of distal hereditary polyneuropathy is Charcot-Marie-Tooth disease (CMT). CMT is a motor sensory polyneuropathy that by definition has sensory involvement and abnormal sensory nerve action potentials. However, the purely motor symptoms and family history in our patient lead to a strong suspicion of dHMN, a subtype of hereditary neuropathy with clinical and genetic overlap with CMT. The cardinal feature of dHMN is a very slowly progressive length-dependent neuropathy often starting in the first 2 decades,² although later onset has been reported.³ There are multiple genes associated with dHMN; however, a causative genetic defect can currently only be identified in fewer than 20% of patients. Bilateral foot drop is only rarely a sole manifestation of a hereditary neuromuscular junction (NMJ) disorder or congenital myasthenic syndrome, and is therefore unlikely. One such recently described congenital myasthenic syndrome/dHMN overlap is due to mutations in synaptotagmin 2 (SyT2), manifesting with distally dominant weakness, foot deformities, and presynaptic NMJ dysfunction on postexercise compound muscle action potential (CMAP) amplitude testing.⁴ Foot drop can be the dominant manifestation of hereditary distal myopathies such as myofibrillar myopathy and GNE myopathy.⁵ Myofibrillar myopathies are clinically and genetically (genes associated include MYOT, DES, CRYAB, ZASP, FLNC, and BAG3) heterogeneous disorders characterized by progressive muscle weakness with typical onset in mid-adulthood.⁵ GNE myopathy typically presents with weakness of ankle dorsiflexion in early to mid-adulthood.⁶ Differentiating a distal myopathy and dHMN can be challenging. Frequently, initially affected upper extremity muscles include intrinsic hand muscles in dHMN and forearm/finger flexors in distal myopathies.² However, as in the current case, when the patient presents with isolated foot drop, diagnosis based on phenotype becomes difficult and warrants further evaluation such as electrodiagnostic testing, which can be key for etiologic delineation.

Investigations in our patient revealed a normal serum creatine kinase (CK) level, hemoglobin A1c level, thyroid function, vitamin B₁₂, and protein immunofixation electrophoresis. Nerve conduction studies showed a low amplitude tibial CMAP, with otherwise normal motor and sensory conduction studies for age. EMG examination revealed increased abnormal spontaneous activity and severely reduced recruitment of tibialis anterior and medial gastrocnemius muscles (table). These findings were suggestive of chronic axonal neuropathy.

Section 3

Based on the clinical presentation, family history, and electrodiagnostic results, dHMN was strongly considered in our patient. He underwent next-generation sequencing and deletion/duplication analysis targeted to genes known to be associated with hereditary neuropathies, which showed a heterozygous variant of unknown significance (p.Pro682Leu; c.2045C>T) in MED25 (mediator complex subunit 25). The MED25 gene is associated with CMT disease type 2B (CMT2B). CMT2B is an autosomal recessive axonal neuropathy characterized by distal weakness, mild sensory loss, and normal or near normal nerve conduction velocities. Disease manifestation occurs only in a homozygous or compound heterozygous state, making this an unlikely explanation in our patient.⁷ We proceeded with whole-exome sequencing (WES) for precise diagnosis. WES revealed a heterozygous known pathogenic variant p. Ser60Cys (c.179C>G) in the MYOT gene. This has been reported previously in patients with myofibrillar myopathy. This variant is not observed in large population cohorts and functional studies indicate that S60C results in the reduced degradation of myotilin.⁸